Project 4: Exercise and Metformin to Impact Hyperinsulinemia in Colorectal Cancer Survivors Summary Observational evidence suggests that factors related to energy balance, including exercise, body weight and diet, may be related not only to the risk of developing colorectal cancer, but also to prognosis in patients who develop the disease. One hypothesis for the impact of these factors on colorectal cancer tumorigenesis and prognosis is related to hyperinsulinemia and insulin-like growth factors. Several studies have demonstrated that colon cancer risk and recurrence rates are elevated in individuals with higher circulating levels of insulin or C-peptide as well as in individuals with higher levels of insulin-like growth factor (IGF)-I or lower levels of IGF binding protein (IGFBP)-3. However, there are no data testing strategies to lower levels of insulin or related hormones in colorectal cancer survivors. Two strategies that have strong scientific rationale to impact on the insulin-related pathways are exercise intervention and metformin. Exercise has consistently been shown in observational studies to reduce the hsk of developing colorectal cancer and, more recently, risk of cancer recurrence and colorectal-cancer related mortality. Metformin reduces hyperinsulinemia and activates the AMP-activated protein kinase (AMPK) which suppresses a variety of pathways. In project 4, we propose a 2 x 2 randomized trial of supervised aerobic exercise guided by validated behavioral support techniques versus attention control and metformin versus placebo in stage l - l l l colorectal cancer patients within 2 years of completion of therapy. The primary objective will be to determine whether supervised exercise training alone and metformin, either alone or in combination, can decrease fasting insulin level from baseline to 6 months in patients who completed standard therapy for stage I - III colorectal cancer. Secondary objectives include (1) comparing changes in other insulin-related biomarkers, (2) explore for an interaction effect in addition to an additive effect of exercise and metformin in reducing fasting insulin level over the 6 month intervention, (3) compare changes in body composition as well as self-directed change in diet quality, (4) compare changes in pro-inflammatory markers related to insulin resistance, (5) determine whether the theoretical constructs of the theory of planned behavior predict change in exercise behavior.